Fibronectins, and other components of the extracellular matrix, influence cell adhesion and migration, and mediate signaling via cell surface integrin receptors. FN variants are generated from alternative transcripts from a single gene. These variants are expressed with tissue and developmental stage specificity, which suggests, but does not demonstrate, that the alternative domains are functional. One such alternative domaine is termed EIIIA in rodents, and ED1 in human nomenclature. Our working hypothesis is that the multifunctional nature of Fns is derived at least partly from alternative exons. This idea is evident in the distinctive phenotypes of FN.null and EIIIA.minus mutant mice, which we have recently generated. FN.null mice, which lack all FN variants, die during gastrulation, with defects in multiple tissues including the cardiovascular system. We have recently determined that a mutation in EIIIA (EIIIA.minus) also causes animals to die before birth, but at a much later stage than if all Fns were lacking. Theses results suggest a specific role for the EIIIA domain in the functions of FN later in development. In adult disease, FN alternative domains are re-expressed during wound healing in several different tissues. Recently, the EIIIA domain has been shown, in vitro, to have biological function during liver wound repair, and appears to be involved in the conversion of lipocytes to myofibroblasts. This conversion is the initial step in the process towards pathological fibrosis of the liver. An animal model in which this process is modified may lead to mechanistic analysis, and may reveal novel targets for therapeutic intervention. Thus, the overall goal of this application is to investigate the roles of FN alternative splice variants in development and adult physiology. The primary goals are 1) To determine the primary mechanisms of defects observed in early embryos which lack all FN variants. 2) To characterize the defects in fetal mice, when either EIIIA-plus or EIIIA-minus Fns are lacking. 3) To develop a viable adult EIIIA.minus mouse model, with EIIIA deficiency in liver, to investigate the in vivo roles of EIIIA-plus Fns during liver would repair.